Abstract:
Tissue-resident memory T cells (TRM) persist locally in non-lymphoid tissues, providing front-line defense against recurring insults. However, strict tissue compartmentalization of memory may pose certain disadvantages for a large barrier organ like the skin, and the long-term migratory behaviour of human TRM and their contribution to the memory pool have not been fully elucidated. TRM at barrier surfaces are defined in part by expression of the markers CD103 and/or CD69 which function to retain TRM in epithelial tissues. Here, we found that CD4+CD69+CD103+ TRM in human skin can downregulate CD69, exit the tissue and be identified as a phenotypically unique population in the circulation of healthy individuals. These circulating TRM produce the cytokines IL-22 and IL-13, and express genes consistent with a role in host-defense and tissue-repair responses. RNA‐ and TCR-sequencing demonstrated that CD103+ TRM in the blood are transcriptionally and clonally related to CD69+CD103+ TRM in the skin. Furthermore, using a skin xenograft model, we confirmed that human cutaneous CD103+ TRM can exit the skin, enter the circulation, and recirculate to secondary human skin sites where they re-assume a TRM phenotype. Thus, although as a population CD4+ TRM in the skin are largely sessile, recirculation of cutaneous CD4+CD103+ TRM does occur in the steady state in humans, and these recirculating (rc)TRM cells can promote the spread of this functionally specialized T cell population throughout the skin.
One Sentence Summary: Functionally specialized human CD4+ cutaneous resident memory T cells have the ability to exit the skin, are found in the circulation of healthy subjects, and can seed distant skin sites.